Proteolipid protein (PLP) is the major protein component of CNS myelin and appears to be a major target of immune responses both in murine models of experimental autoimmune encephalomyelitis (EAE) and perhaps in human multiple sclerosis (MS). A chronic-relapsing form of EAE (R- EAE) is induced in inbred SJL/J mice following either active immunization with intact PLP of the major encephalitogenic determinant of the PLP molecule which encompasses amino acids 139-151 (PLP139-151), or the adoptive transfer of T cell lines/clones specific for the PLP139-151 epitope. PLP-induced R-EAE follows a relapsing-remitting course of paralysis and is characterized histologically by perivascular mononuclear cell-rich infiltrates of the white matter of the central nervous system (CNS) and areas of acute and chronic demyelination. The well-understood genetics of the murine host and the similarities in both clinical course and histopathology of murine R-EAE and MS make it an ideal animal model for the study of immunoregulatory aspects of oral tolerance. We will address the cellular and molecular mechanisms of oral tolerance induction by the intragastric (i.g.) administration of PLP and PLP139-151. Our central hypothesis is that oral antigen administration induces anti-inflammatory cytokine expression patterns that result in systemic immune tolerance. This anti-inflammatory cytokine expression regulates costimulatory molecule expression, inflammatory cytokine expression, and lymphoid cell trafficking events. This hypothesis will be tested by the following specific aims: 1) examination of oral antigen regulation of costimulatory molecule expression; 2) combinatorial use of oral antigen administration and costimulatory molecules antagonists for the treatment of ongoing EAE; 3) examination of cytokine regulation of oral tolerance induction during ongoing and relapsing EAE; and 4) examination of antigen-specific T cell trafficking after antigen feeding, including cytokine and adhesion molecule regulation of lymphocyte trafficking patterns. These studies should lead to a better understanding of the immunoregulatory mechanisms of oral tolerance which could potentially be used to control pathologic T cell-mediated immune responses.